Bio

Bio

My primary research focus is in translational molecular virology and drug discovery/development. My work aims to uncover and characterize novel virus targets for the rational design of new classes of antiviral therapeutics.

Honors & Awards

  • Postdocs at the Interface Seed Grant Award, Stanford ChEM-H (Chemistry, Engineering & Medicine For Human Health) (2019)
  • Stanford SIGF Bio-X Interdisciplinary Graduate Fellowship Award, Stanford University (2014-2017)
  • SPARK/Spectrum Innovation Accelerator Seed Grant Award in Therapeutics, Stanford University, SPARK Program (2014-2015)
  • NIAID Merit Award for achievements associated with research on 2009 H1N1 pandemic influenza virus, National Institutes of Allergy & Infectious Diseases (2009)
  • Research Fellowship Training Award, National Institutes of Health (2008-2010)
  • WELCH Chemistry Undergraduate Research Grant, The WELCH Foundation (2005-2006)
  • Honor Society Member, Alpha Sigma Lambda (2005-)

Education & Certifications

  • PhD, Stanford University School of Medicine, Microbiology & Immunology (2018)
  • B.S., St. Edward's University, Biochemistry (2006)
  • B.A., St. Edward's University, Philosophy (2006)

Contact

Publications

All Publications

  • RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses: a first look. RNA (New York, N.Y.) Rangan, R., Zheludev, I. N., Das, R. 2020

    Abstract

    As the COVID-19 outbreak spreads, there is a growing need for a compilation of conserved RNA genome regions in the SARS-CoV-2 virus along with their structural propensities to guide development of antivirals and diagnostics. Here we present a first look at RNA sequence conservation and structural propensities in the SARS-CoV-2 genome. Using sequence alignments spanning a range of betacoronaviruses, we rank genomic regions by RNA sequence conservation, identifying 79 regions of length at least 15 nucleotides as exactly conserved over SARS-related complete genome sequences available near the beginning of the COVID-19 outbreak. We then confirm the conservation of the majority of these genome regions across 739 SARS-CoV-2 sequences subsequently reported from the COVID-19 outbreak, and we present a curated list of 30 'SARS-related-conserved' regions. We find that known RNA structured elements curated as Rfam families and in prior literature are enriched in these conserved genome regions, and we predict additional conserved, stable secondary structures across the viral genome. We provide 106 'SARS-CoV-2-conserved-structured' regions as potential targets for antivirals that bind to structured RNA. We further provide detailed secondary structure models for the extended 5' UTR, frame-shifting element, and 3' UTR. Last, we predict regions of the SARS-CoV-2 viral genome that have low propensity for RNA secondary structure and are conserved within SARS-CoV-2 strains. These 59 'SARS-CoV-2-conserved-unstructured' genomic regions may be most easily targeted in primer-based diagnostic and oligonucleotide-based therapeutic strategies.

    View details for DOI 10.1261/rna.076141.120

    View details for PubMedID 32398273

  • Cryo-electron Microscopy and Exploratory Antisense Targeting of the 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome. bioRxiv : the preprint server for biology Zhang, K., Zheludev, I. N., Hagey, R. J., Wu, M. T., Haslecker, R., Hou, Y. J., Kretsch, R., Pintilie, G. D., Rangan, R., Kladwang, W., Li, S., Pham, E. A., Bernardin-Souibgui, C., Baric, R. S., Sheahan, T. P., D Souza, V., Glenn, J. S., Chiu, W., Das, R. 2020

    Abstract

    Drug discovery campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are beginning to target the viral RNA genome 1, 2 . The frameshift stimulation element (FSE) of the SARS-CoV-2 genome is required for balanced expression of essential viral proteins and is highly conserved, making it a potential candidate for antiviral targeting by small molecules and oligonucleotides 3-6 . To aid global efforts focusing on SARS-CoV-2 frameshifting, we report exploratory results from frameshifting and cellular replication experiments with locked nucleic acid (LNA) antisense oligonucleotides (ASOs), which support the FSE as a therapeutic target but highlight difficulties in achieving strong inactivation. To understand current limitations, we applied cryogenic electron microscopy (cryo-EM) and the Ribosolve 7 pipeline to determine a three-dimensional structure of the SARS-CoV-2 FSE, validated through an RNA nanostructure tagging method. This is the smallest macromolecule (88 nt; 28 kDa) resolved by single-particle cryo-EM at subnanometer resolution to date. The tertiary structure model, defined to an estimated accuracy of 5.9 Å, presents a topologically complex fold in which the 5' end threads through a ring formed inside a three-stem pseudoknot. Our results suggest an updated model for SARS-CoV-2 frameshifting as well as binding sites that may be targeted by next generation ASOs and small molecules.

    View details for DOI 10.1101/2020.07.18.209270

    View details for PubMedID 32743589

    View details for PubMedCentralID PMC7386510

  • Reconstitution and Functional Analysis of a Full-Length Hepatitis C Virus NS5B Polymerase on a Supported Lipid Bilayer. ACS central science Cho, N., Pham, E. A., Hagey, R. J., Lévêque, V. J., Ma, H., Klumpp, K., Glenn, J. S. 2016; 2 (7): 456-466

    Abstract

    Therapeutic targeting of membrane-associated viral proteins is complicated by the challenge of investigating their enzymatic activities in the native membrane-bound state. To permit functional characterization of these proteins, we hypothesized that the supported lipid bilayer (SLB) can support in situ reconstitution of membrane-associated viral protein complexes. As proof-of-principle, we selected the hepatitis C virus (HCV) NS5B polymerase which is essential for HCV genome replication, and determined that the SLB platform enables functional reconstitution of membrane protein activity. Quartz crystal microbalance with dissipation (QCM-D) monitoring enabled label-free detection of full-length NS5B membrane association, its interaction with replicase subunits NS3, NS5A, and template RNA, and most importantly its RNA synthesis activity. This latter activity could be inhibited by the addition of candidate small molecule drugs. Collectively, our results demonstrate that the SLB platform can support functional studies of membrane-associated viral proteins engaged in critical biological activities.

    View details for DOI 10.1021/acscentsci.6b00112

    View details for PubMedID 27504492

  • The natural history of influenza infection in the severely immunocompromised vs nonimmunocompromised hosts. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Memoli, M. J., Athota, R., Reed, S., Czajkowski, L., Bristol, T., Proudfoot, K., Hagey, R., Voell, J., Fiorentino, C., Ademposi, A., Shoham, S., Taubenberger, J. K. 2014; 58 (2): 214?24

    Abstract

    Medical advances have led to an increase in the world's population of immunosuppressed individuals. The most severely immunocompromised patients are those who have been diagnosed with a hematologic malignancy, solid organ tumor, or who have other conditions that require immunosuppressive therapies and/or solid organ or stem cell transplants.Medically attended patients with a positive clinical diagnosis of influenza were recruited prospectively and clinically evaluated. Nasal washes and serum were collected. Evaluation of viral shedding, nasal and serum cytokines, clinical illness, and clinical outcomes were performed to compare severely immunocompromised individuals to nonimmunocompromised individuals with influenza infection.Immunocompromised patients with influenza had more severe disease/complications, longer viral shedding, and more antiviral resistance while demonstrating less clinical symptoms and signs on clinical assessment.Immunocompromised patients are at risk for more severe or complicated influenza induced disease, which may be difficult to prevent with existing vaccines and antiviral treatments. Specific issues to consider when managing a severely immunocompromised host include the development of asymptomatic shedding, multi-drug resistance during prolonged antiviral therapy, and the potential high risk of pulmonary involvement.ClinicalTrials.gov identifier NCT00533182.

    View details for DOI 10.1093/cid/cit725

    View details for PubMedID 24186906

    View details for PubMedCentralID PMC3871797

  • Multidrug-resistant 2009 Pandemic Influenza A Viruses Maintain Fitness and Transmissibility in Ferrets Multidrug-resistant 2009 Pandemic Influenza A Viruses Maintain Fitness and Transmissibility in Ferrets Memoli, M., Davis, A., Proudfoot, K., Chertow, D., Hagey (Hrabal), R. J., Bristol, T., Taubenberger, J. K. 2011; 203 (3)

    View details for DOI 10.1093/infdis/jiq067

  • The PB2-E627K Mutation Attentuates Viruses Containing the 2009 H1N1 Influenza Pandemic Polymerase The PB2-E627K Mutation Attentuates Viruses Containing the 2009 H1N1 Influenza Pandemic Polymerase Jagger, B. W., Memoli, M. J., Sheng, Z., Qi, L., Hagey (Hrabal), R. J., Allen, G. L., Dugan, V. G., Wang, R., Digard, P., Kash, J. C., Taubenberger, J. K. 2010; 1 (1)

    View details for DOI 10.1128/mBio.00067-10

  • Rapid Selection of Oseltamivir- and Peramivir-Resistant Pandemic H1N1 Virus during Therapy in 2 Immunocompromised Hosts Rapid Selection of Oseltamivir- and Peramivir-Resistant Pandemic H1N1 Virus during Therapy in 2 Immunocompromised Hosts Memoli, M., Hagey (Hrabal), R. J., Hassantoufighi, A., Eichelberger, M. C., Taubenberger, J. K. 2010; 50 (9): 1252-1255

    View details for DOI 10.1086/651605

  • Rapid Selection of a Transmissible Multidrug-Resistant Influenza A/H3N2 Virus in an Immunocompromised Host Rapid Selection of a Transmissible Multidrug-Resistant Influenza A/H3N2 Virus in an Immunocompromised Host Memoli, M. J., Hagey (Hrabal), R. J., Hassantoufighi, A., Jagger, B. W., Sheng, Z., Eichelberger, M. C., Taubenberger, J. K. 2010; 201 (9): 1397-1403

    View details for DOI 10.1086/651610

  • Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus Kash, J. C., Qi, L., Dugan, V. G., Jagger, B. W., Hagey (Hrabal), R. J., Memoli, M. J., Morens, D. M., Taubenberger, J. K. 2010; 4 (3): 121-127

    View details for DOI 10.1111/j.1750-2659.2010.00132.x

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